Co-reporter:Shuting Chen, Ying Zhang, Xiaoyan Li, Hongmei Jia, Jie Lu
Bioorganic & Medicinal Chemistry Letters 2017 Volume 27, Issue 15(Issue 15) pp:
Publication Date(Web):1 August 2017
DOI:10.1016/j.bmcl.2017.05.053
A triphenylphosphonium cation, [99mTc]Technetium cyclopentadienyltricarbonyl-6-hexanoyl-triphenylphosphonium cation ([99mTc]3) was prepared to target multidrug resistance (MDR). The radiotracer was evaluated in the MDR-negative MCF-7 and MDR-positive MCF-7/ADR cell lines in vitro, as well as animal models in vivo. [99mTc]3 was proofed to be a substrate of P-glycoprotein and multidrug resistant protein 1, and showed a higher accumulation in the MDR-negative MCF-7 cells compared to 99mTc-sestamibi in vitro. The MCF-7 tumor-to-MCF-7/ADR tumor ratio of [99mTc]3 was ∼3 at 1 h p.i. in the biodistribution study. These results demonstrated the capability of the radiotracer to detect multidrug resistance in tumor cells.Download high-res image (100KB)Download full-size image
Co-reporter:Xuran Zhang;Qian Yu;Yingfang He;Chun Zhang;Hua Zhu;Zhi Yang
Journal of Labelled Compounds and Radiopharmaceuticals 2016 Volume 59( Issue 9) pp:346-353
Publication Date(Web):
DOI:10.1002/jlcr.3410
In order to develop novel 68Ga-labeled PET tracers for folate receptor imaging, two DOTA-conjugated Pteroyl-Lys derivatives, Pteroyl-Lys-DOTA and Pteroyl-Lys-DAV-DOTA, were designed, synthesized and radiolabeled with 68Ga. Biological evaluations of the two radiotracers were performed with FR-positive KB cell line and athymic nude mice bearing KB tumors. Both 68Ga-DOTA-Lys-Pteroyl and 68Ga-DOTA-DAV-Lys-Pteroyl exhibited receptor specific binding in KB cells in vitro. The tumor uptake values of 68Ga-DOTA-Lys-Pteroyl and 68Ga-DOTA-DAV-Lys-Pteroy were 10.06 ± 0.59%ID/g and 11.05 ± 0.60%ID/g at 2 h post-injection, respectively. Flank KB tumor was clearly visualized with 68Ga-DOTA-DAV-Lys-Pteroyl by Micro-PET imaging at 2 h post-injection, suggesting the feasibility of using 68Ga-labeled Pteroyl-Lys conjugates as a novel class of FR targeted probes.
Co-reporter:Fang Xie, Chun Zhang, Qian Yu, Yan Pang, Yuan Chen, Wenjiang Yang, Jingquan Xue, Yu Liu and Jie Lu
RSC Advances 2014 vol. 4(Issue 61) pp:32197-32206
Publication Date(Web):30 Jun 2014
DOI:10.1039/C4RA03564J
In order to develop a novel 99mTc-labeled folate based SPECT radiotracer with an optimized pharmacokinetic profile for the folate receptor (FR) positive tumor imaging, a folate conjugate, HYNIC-PEG2-FA, was designed, synthesized and radiolabeled with 99mTc using tricine/diphenylphosphinobenzene-3-sulfonic acid sodium (TPPMS), tricine/trisodium triphenylphosphine-3,3′,3′′-trisulfonate (TPPTS), and ethylenediamine-N,N′-diacetic acid (EDDA) as coligands. 99mTc(HYNIC-PEG2-FA)(tricine/TPPTS), 4, 99mTc(HYNIC-PEG2-FA)(tricine/TPPMS), 5 and 99mTc(HYNIC-PEG2-FA)(EDDA), 6, were obtained respectively. All of them were stable in saline and mouse plasma for 6 h, and displayed high specific binding in the FR-positive KB cell line in vitro. Among them, complex 4 exhibited a higher tumor uptake (11.35 ± 0.67 ID% g−1 at 2 h p.i.) and more rapid clearance from the liver, lungs, blood, muscle and other non-target organs than 99mTc (HYNIC-NHHN-FA)(tricine/TPPTS), which we reported before. Small animal SPECT/CT imaging studies in FR-positive KB tumor models showed that the tumor could be clearly visualized at 120 min p.i., suggesting its potential as a promising folate receptor targeting agent for tumor imaging.
Co-reporter:Yuan Chen;Hongjuan Guo;Fang Xie
Journal of Labelled Compounds and Radiopharmaceuticals 2014 Volume 57( Issue 1) pp:12-17
Publication Date(Web):
DOI:10.1002/jlcr.3116
In order to develop a novel 99mTc-labeled folate receptor (FR) imaging agent, a dithiocarbamate derivative, pteroyl-lys-DTC, was synthesized and radiolabeled with 99mTc through the [99mTcN]2+ intermediate. The radiochemical purity of the corresponding 99mTc-complex, 99mTcN-pteroyl-lys-DTC, was over 95% as measured by reversed-phase HPLC. The 99mTcN complex was stable under physiological conditions. 99mTcN-pteroyl-lys-DTC exhibited specific FR binding in FR-positive KB cells in vitro. The biodistribution in tumor-bearing mice showed that the 99mTcN-labeled radiotracer had good uptake (3.56 ± 0.09%ID/g at 2 h postinjection) in FR-positive KB tumors, as well as in the kidneys (30.34 ± 3.53%ID/g at 2 h postinjection). After coinjection with excess folic acid, the uptake in tumor and kidneys was significantly blocked. The results indicated that 99mTcN-pteroyl-lys-DTC was able to target the FR-positive tumor cells and tissues specifically both in vitro and in vivo. Copyright © 2013 John Wiley & Sons, Ltd.
Co-reporter:Hongjuan Guo, Fang Xie, Meilin Zhu, Yan Li, Zhi Yang, Xuebin Wang, Jie Lu
Bioorganic & Medicinal Chemistry Letters 2011 Volume 21(Issue 7) pp:2025-2029
Publication Date(Web):1 April 2011
DOI:10.1016/j.bmcl.2011.02.014
Aiming to develop a new 99mTc-labeled folate derivative for FR-positive tumor imaging, a simpler method has been established to synthesize the folate-drug conjugates with free α-carboxyl group. In this study, the conjugate pteroyl-lys-HYNIC was synthesized and labeled with 99mTc using tricine and TPPTS as co-ligands. The radiochemical purity of the final complex 99mTc(HYNIC-lys-pteroyl)(tricine/TPPTS), 5 was high (>98%), and it remained stable in saline and plasma over 6 h after preparation. The biologic evaluation results showed that the 99mTc labeled pteroyl-lys conjugate was able to specifically target the FR-positive tumor cells and tissues both in vitro and in vivo, highlighting its potential as an effective folate receptor targeted agent for tumor imaging.The novel complex 99mTc(HYNIC-lys-pteroyl)(tricine/TPPTS) was able to specifically target the FR-positive tumor cells and tissues both in vitro and in vivo, highlighting its potential as an effective folate receptor targeted agent for tumor imaging.
Co-reporter:Jie Lu;Mingyan Xu;Hongmei Jia;Shuxia Xi;Yimeng Wang;Xuebin Wang
Journal of Labelled Compounds and Radiopharmaceuticals 2009 Volume 52( Issue 6) pp:183-188
Publication Date(Web):
DOI:10.1002/jlcr.1587
Abstract
Three dithioformate ligands with methyl substituted on the piperidine rings, potassium 1-(2-methylpiperidine-1-yl)-dithioformate (2-mp), potassium 1-(3-methylpiperidine-1-yl)-dithioformate (3-mp) and potassium 1-(4-methylpiperidine-1-yl)-dithioformate (4-mp) were synthesized. The corresponding 99mTc-nitrido complexes were prepared in high yield (>95%) through the [99mTcN] intermediate and characterized by thin layer chromatography and high-performance liquid chromatography. All the neutral 99mTc-nitrido complexes were stable under physiological conditions and lipophilic with log P values between 1.40 and 1.58. In vivo biodistribution results showed that all the 99mTc-nitrido complexes displayed high brain uptakes and long retention times. Among them, 99mTcN-4mp, demonstrated the best properties for brain imaging with the brain uptake 3.40±0.24, 3.22±0.31, 2.72±0.28 and 2.22±0.18% ID/g at 5, 30, 60 and 120 min p.i., respectively. Moreover, the influence of stereochemistry of the 99mTcN complexes with methyl substitution on ortho, meta and para positions on piperidine ring on the biodistribution properties were investigated with B3LYP/6-31G*(LANL2DZ for Tc) method using the Gaussian 03 program package. Copyright © 2009 John Wiley & Sons, Ltd.
Co-reporter:Dejing Kong;Xuebin Wang;Shuzhang Ye
Journal of Labelled Compounds and Radiopharmaceuticals 2007 Volume 50(Issue 13) pp:1137-1142
Publication Date(Web):31 AUG 2007
DOI:10.1002/jlcr.1292
The novel dithiocarbamate derivative of metronidazole, potassium 2-(2-methyl-5-nitro-1H-imidazolyl)-ethyl-dithiocarbamate (MNIE-DTC), was synthesized as the pharmacophore-containing bifunctional ligand. The corresponding asymmetrical 99mTc-nitrido complex, expected as a tumor hypoxia marker, had been successfully obtained by the addition of the biphosphine ligand PNP5 (PNP5 = N-ethoxethyl-N,N-bis[2-(bis(3-methoxypropyl)phosphino)ethyl]-amine) and the dithiocarbamate ligand (MNIE-DTC) to the 99mTc-nitrido precursor solution at 100°C for 15 min. The radiochemical purity of the product was above 95% as measured by thin-layer chromatography and high-performance liquid chromatography. In vitro studies showed that the complex possessed good stability under physiological conditions. Its partition coefficient studies indicated that it was a lipophilic complex. The electrophoresis results showed that the complex was cationic. Biological evaluation of the complex [99mTcN(PNP5)(MNIE-DTC)]+ performed in Kunming mice bearing H22 tumor showed that the complex had a moderate tumor uptake (0.57±0.06%ID/g at 1h), and the ratios of tumor/blood and tumor/muscle were 2.46 and 1.31 at 1h p.i., and reached 4.52 and 2.86 at 4h p.i., respectively. Copyright © 2007 John Wiley & Sons, Ltd.
Co-reporter:Jie Lu;Dejing Kong;Hongmei Jia;Peter Brust;Xuebin Wang;Winnie Deuther-Conrad
Journal of Labelled Compounds and Radiopharmaceuticals 2007 Volume 50(Issue 13) pp:1200-1205
Publication Date(Web):19 SEP 2007
DOI:10.1002/jlcr.1438
The goal of this study is to develop a novel 99mTc-labeled σ receptor imaging agent. Potassium 4-(cyclohexylpiperazin-1-yl)-dithioformate, 2, and the corresponding rhenium complex, ReN-2, were synthesized and characterized. ReN-2 possessed moderate affinity toward σ1 (Ki = 1.94 ± 0.60 µmol/L) and σ2 (Ki = 2.83 ± 1.39 µmol/L) receptors. The radiolabeled complex 99mTcN-2 was prepared in high yield (> 95%) through the [99mTcN] precursor and characterized by HPLC. 99mTcN-2 was found to be a lipophilic and neutral complex with good stability. The biodistribution in tumor-bearing mice showed that 99mTcN-2 had good tumor uptake (2.12 ± 0.01 %ID/g at 2 h p.i.) and moderate brain uptake (0.27 ± 0.05 %ID/g at 2 h p.i.). After blocking with haloperidol, the uptakes by tumor and brain were lower than control. The results indicated that the complex has specific binding to the σ receptors in vivo. Further structural modifications of this complex are needed to obtain 99mTc-based σ receptor imaging agents with high affinity and subtype selectivity. Copyright © 2007 John Wiley & Sons, Ltd.
Co-reporter:Jie Lu, Dejing Kong, Zhao Yang, Shuye Yang, Weiwei Fan, Hongmei Jia, Xuebin Wang
Applied Radiation and Isotopes (October 2007) Volume 65(Issue 10) pp:1134-1139
Publication Date(Web):October 2007
DOI:10.1016/j.apradiso.2007.04.021
Co-reporter:Shuting Chen, Zuoquan Zhao, Ying Zhang, Wei Fang, ... Xianzhong Zhang
Nuclear Medicine and Biology (June 2017) Volume 49() pp:16-23
Publication Date(Web):1 June 2017
DOI:10.1016/j.nucmedbio.2017.02.002
Introduction18F–labeled phosphonium cations targeting mitochondrial membrane potential would be promising for positron emission tomography (PET) myocardial perfusion imaging (MPI). The purpose of this study was to examine the influence of additional methoxy group and its different positions on myocardium uptake and pharmacokinetics properties of 18F–labeled benzyl triphenylphosphonium cations.MethodIn this study, three novel 18F–labeled phosphonium cations, [18F]4-(fluoromethyl)benzyltris(4-methoxyphenyl) phosphonium cation (1b), [18F]4-(fluoromethyl)benzyltris(2-methoxyphenyl) phosphonium cation (2b) and [18F]4-(fluoromethyl)benzyltris(3-methoxyphenyl) phosphonium cation (3b), were efficiently prepared by a One-Pot method starting from the substitution of non-carried-added fluoride-18. Radiotracers were purified by HPLC. Physicochemical properties, in vitro cell uptake assay, in vivo mice biodistribution and rat micro-PET imaging were investigated.ResultsResults suggested that the position of methoxy group exhibited significant effect on the biological properties of 18F–labeled benzyl triphenylphosphonium cations. The addition of methoxy group on orth- or meta-position of the radiotracers accelerated the radioactivity clearance from liver. The para-radiotracer had the highest uptake in the heart and other non-targeting organs. According to the biodistribution data, 2b (ortho-) displayed the fastest liver clearance and highest heart-to-background ratios. And its rat micro-PET images at 60 min post-injection revealed a good visualization of heart and favorable heart-to-background contrast. Nevertheless, 2b exhibited a lower initial liver uptake and quicker liver clearance compared with 99mTc-sestamibi.ConclusionThe ortho- compound (2b) displayed the most favorable biological properties as a potential MPI agent to acquire high contrast images early after injection.Download high-res image (84KB)Download full-size image
